The chief goal of this study is to identify the components of the spectrum of mood disorders using methods of genetic epidemiology, developmental psychopathology and clinical psychiatry/psychology. One of the chief issues addressed in our work is identifying the core clinical and biologic factors underlying mood disorder spectrum and migraine that run in families. The phases of implementation of this research include: (1) development of measures of the spectrum of mood and anxiety disorders in adults and children, and structured interviews for the key components of the study phenotypes including mood, sleep and headache;(2) sampling and recruitment of probands from both clinical and community settings and enrollment and evaluation of the relatives;(3) selection and implementation of core features and endophenotypes for mood disorders and migraine;and (4) establishment of a high risk cohort to study the evolution of these disorders and the specificity of vulnerability markers and endophenotypes prior to clinical onset of these conditions. Phase I: Development of Measures We have now completed the first phase of our study in both adults and children. Phase II: Recruitment We recruit participants into our study from both clinical settings and the greater Washington, D.C. community. The community recruitment helps create an unbiased sample for our family study to further enhance the generalizability of our study findings to the population. To date, we have enrolled 340 participants into the study from the community, and 216 from clinical sources. Our total enrollment from all sources is 763 probands and 1001 relatives, including 150 children. Over the past year 81 probands and 214 relatives have been recruited. Probands represent a range of disorders including: 22% with bipolar disorder, 46% with depression, 52% with anxiety, 45% with migraine, and 34% are controls. Phase III: Clinical Components and Endophenotypes In order to identify the core features of mood and anxiety disorders and their overlap with cardiovascular diseases and migraine, we have established a set of clinical, psychophysiological and neuropsychological measures. We collect data on biologic rhythms including sleep, eating, and physical activity (as measured by actigraphy). Electronic diaries (experiential sampling) are used to query symptoms of headache, mood and anxiety multiple times daily as well as current life activities. The use of electronic diaries in combination with actigraphy is unique and novel in that it is a method of validating anecdotal associations that have previously been based on retrospective reports that are prone to individual interpretation and bias. The data we have collected to date provides some exciting findings regarding the extent to which physical activity can actually reduce depressed mood. In order to evaluate differences in stress reactivity, we also measure cortisol(a stress hormone) levels in saliva during the two week period in which the participants are completing the electronic diaries. To date, we have collected saliva in 150 participants. We also assess autonomic nervous system functioning, which is the part of the nervous system that controls energy mobilization during a reaction to stress using a 24-hour heart monitor and a test of blood pressure and stress hormones during a tilt table test. This procedure has been completed in 294 participants. Another clinical component of our study is measuring the structure of the brain using a 1.5t structural MRI. In collaboration with Drs. Karen Berman, Wayne Drevets, and Nicholas Patronas we have completed two independent ratings for each participant of white matter hyperintensities (WMHs), and other brain structures that have been shown to be associated with migraine and depression. Preliminary results of 232 participants suggest that there are a greater number of WMHs in people with a history of depression. We have also assessed several psychophysiological measures including the nociceptive eye-blink reflex and the emotional modulation of the startle reflex. The startle reflex is a sensitive probe to emotional states and patients with anxiety disorders show altered physiological reactions to certain types of emotional modulation of the startle reflex. We have established a new startle paradigm that can be used across all ages. First results on gender differences in reactions to fear and anxiety provoking stimuli in children are currently under review for publication. In collaboration with Raquel Gur, M.D., Ph.D., and Ruben Gur, Ph.D. at the University of Pennsylvania, we have developed and administered a computerized battery of neuropsychological measures assessing attention, memory, perception, decision making, and general cognitive function in our participants. Deficits and abnormalities in these domains have been long associated with migraine, mood, and anxiety disorders. Ascertaining such an extensive neuropsychological profile in a family study setting gives us added power that is unique to our study and allows us to better understand the disorders in question. Preliminary findings of these studies indicate that, relative to unaffected individuals, individuals with Bipolar I disorder show deficits in smell discrimination, and individuals with migraine show deficits in smell identification. In addition, we found that individuals with migraine (without aura) demonstrate reduced performance on an executive functioning task. These findings have been presented at several local and international conferences, as well as the NIH research festival. During the next year, we will have sufficient numbers to conduct preliminary analyses of familial aggregation of the spectrum of disorders as well as to evaluate whether these measures discriminate between diagnostic subgroups. We can then examine the specificity of these measures in the relatives and offspring. Overall, the combination of these clinical, neuropsychological and psychophysiological measures within families will allow us an in-depth analysis of the biological mechanisms crucial for migraine and mood and anxiety disorders and the common diathesis underlying these domains. This will not only lead to a better understanding of these conditions, and assist in identifying common genetic mechanisms, but may also lead to the development of novel treatment options and possible strategies for prevention and early intervention in those with elevated risk for these conditions. Phase IV: High Risk Study of Offspring Major progress has been achieved during the past year in developing the high risk component of our research. We completed adaptation of the adult clinical and biologic measures for children, and recruited and enrolled 150 youth and their parents in the study. The two sources of recruitment include offspring under age 18 of parents already enrolled in our family study, as well as a new collaboration with the Department of Neurology at the National Childrens Medical Center where we recruit children seeking treatment for headache, and a comparable sample of children from pediatric practices. Initial analyses indicate good to excellent inter-rater reliability of our child diagnostic interview. We are conducting parallel studies of children in the same domains that are being assessed in the adult probands including clinical, psychiatric, physical, neurocognitive, perception, and genetic evaluations. The purpose of the high risk study is to target and recruit offspring of parents with mood spectrum disorders in order to better identify and characterize early signs and symptoms of clinical conditions. Enhancing current understanding of the initial biological and psychological signs of clinical disorder will enable more timely and effective identification and treatment of children at risk.